A relationship exists between the gonads and the thymus. Castration results in a significant increase in the size of the thymus, and elevated serum levels of sex hormones results in a significant decrease in the size of the thymus. This is most evident during pregnancy where serum levels of progesterone and estrogen are very high, and the thymus shrinks to only 10% of its original size. There is also some evidence that the thymus can regulate the gonads. Thymectomized animals and animals congenitally athymic have been reported to have problems with reproduction and gonad function. This is presumably due to limited production of hormones by the thymus. Two lines of thought have developed to explain the thymus-gonad relationship. The most prominent idea is that it must be important to shrink the thymus during pregnancy. This could either be because of a need to limit the production of new T cells, or to limit the production of thymic hormones. The second line of thought is that the thymus and gonads in normal situations regulate each others function as a means to maintain homeostasis. In this case, pregnancy is an exceptional situation where thymic regulation of sex hormones is overcome by other mechanisms. In non-pregnant animals, the thymus limits the production of sex hormones by the gonads, and sex hormones limit the size and function of the thymus so that an optimum output is maintained for both organs. In this proposal, we outline experiments that will test both of these ideas. We propose to: 1) determine the cellular targets for estrogen and progesterone that lead to thymic involution; 2) determine whether the thymus-dependent hormone thymulin can increase levels of estrogen and/or progesterone; and 3) test whether production of new T cells, or production of thymulin, is detrimental to pregnancy.